The invention relates to a biocompatible dialysis membrane for hemodialysis in the form of flat sheets, tubular sheets or hollow filaments, comprising a mixed polysaccharide ester of acetic acid and/or propionic acid and/or butyric acid.
Mixed polysaccharide esters are already known and described in detail in, for example, Kirk-Othmer, "Encyclopedia of Chemical Technology", 2nd Ed., 1964, Vol. 3, pp. 325 ff. Heretofore they have been employed as thermoplastic plastics and in the production of lacquers.
From Japanese Laid-open Application 57-133,211 it is known how to spin cellulose esters such as cellulose diacetate or triacetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate, cellulose acetate butyrate to hollow filaments which are suitable for the purification of body fluids by ultrafiltration and dialysis. Their compatibility with blood is excellent.
The biocompatibility of dialyzers is influenced by numerous factors, of which only one is the membrane, a fact that must not be disregarded in an analysis of the biocompatibility.
Although several biocompatibility parameters with clinical relevance have already been discussed, uncertainties still exist as regards the laboratory values. An important factor in the framework of evaluation of the biocompatibility is the thrombogenicity. Cellulosic membranes are known to have low thrombogenicity, while the thrombogenicity of known cellulose acetate membranes is being seriously evaluated.
In addition to the circumstance that dialysis membranes consisting of synthetic or natural polymers can, during their employment in artificial kidneys, very easily cause coagulation of the blood, which is largely prevented by appropriate drug treatment, there occurs, in the treatment of a kidney patient with dialyzers that contain membranes consisting of regenerated cellulose, a temporary leukocyte decrease in the initial period of the dialysis treatment. This effect is known as leukopenia.
Leukopenia is a lowering of the leukocyte count (white blood corpuscles) in the bloodstream. The number of white blood corpuscles in humans is about 4,000 to 12,000 cells/mm.sup.3.
The leukopenia during dialysis is most strongly pronounced 15 to 20 minutes after the start of the treatment, the neutrophils (which are the leukocytes that can be stained with neutral or simultaneously with acid and basic dyes) being able to disappear almost completely. Thereafter the number of leukocytes recovers to almost the initial value or exceeds it within approximately one hour.
If a new dialyzer is connected after recovery of the leukocytes, leukopenia takes place again to the same extent.
Cellulose membranes cause pronounced leukopenia and cellulose ester membranes cause somewhat less pronounced leukopenia. Although the clinical significance of leukopenia has not been scientifically explained, the wish nevertheless exists for a dialysis membrane for hemodialysis which does not exhibit the effect of leukopenia, without the other greatly desired properties of dialysis membranes being impaired thereby.
In hemodialysis by means of membranes consisting of cellulose and cellulose esters, distinct complement activation has been observed in addition to the leukopenia. The complement system in the blood serum is a complex plasma enzyme system which consists of many components and which acts in various ways in the defense against injuries due to invading foreign cells (bacteria, etc.). If antibodies against the invading organism are present, the antibody with antigenic structures of the foreign cells can be activated in complement specific manner by the complex, otherwise the complement activation takes place by an alternative pathway due to special surface features of the foreign cells. The complement system depends on a large number of plasma proteins. After activation, these proteins react specifically with each other in a particular sequence, and ultimately a cell-damaging complex is formed that destroys the foreign cell.
From individual components there are released peptides, which trigger inflammatory phenomena and sometimes also can have adverse pathological consequences for the organism. It is assumed that the activation in hemodialysis membranes takes place via the alternative pathway. These complement activations are objectively observed by determination of the C3a and C5a complement fragments.
In this connection, reference is made to the following papers: D.E. Chenoweth et al., Kidney International, Vol. 24, page 764 ff., 1983, and D.E. Chenoweth, Asaio-Journal, Vol. 7, page 44 ff., 1984.
Since for cellulose ester membranes the complement activation, measured on the C.sub.5a fragment, is reduced by approximately 50% compared with that of regenerated cellulose membranes, methods have heretofore been searched for and found of reducing, by selective modification, the C.sub.5a fragment for membranes consisting of regenerated cellulose, and in this connection C.sub.5a reductions of up to 80% have been achieved.
An object of the present invention was to achieve a C.sub.5a reduction of 70% and more also for membranes comprising polysaccharide esters.